Process for dehalogenating steroids



United States 2,773,867 PROCESS FOR DEHALOGENATING STEROIDS 14 Claims. '(Cl. 260239.47)

This'inv entionrelates to the dehalogenation of'steroids. More particularly, it relates to the preparation of 17ahydroxypregnenes and allopregnanes, and especially this invention relates to an improved process for the preparation of 17a,21-dihydroxy-20keto-pregnenes. v

In 'the'pre'paratiorrof steroids having the ketol sidechain'at carbon atom 17, the methods involving the use of 16,17-cmpounds have been shown to possess desirable "features. Not only are the 16,l7-epoxy compounds readily obtainable by methods which are practical to operate on a commercial scale, but also such derivatives have been converted by known means to 17oc-hYCl10XY compounds corresponding to the naturally-occurring hormones of the adrenal cortex and intermediates useful in the preparation thereof. Thus, as disclosed in Patent 2,648,663, the 20-cyclic ketals of the l6,17-epoxy pregnenes and -pre'gnanes, upon treatment with a bi hretallic hydride, e. g., lithium aluminum hydride, are converted to the corresponding l7'u-hydroxy compound, which, by acid hydrolysisof the 2 O-ketal, gives'the 17ahydroxy-ZO-keto-pregne'nes and -preg nanes. Similarly, as disclosed in Patent No. 2,662,904, 16,17-epbxy-20-ketopregnenes and pregnanes, upon reduction with a bimetallic hydride, give rise to the corresponding 17a,20-dihydroxypregnene and -pregna'ne Czo-epimeric mixtures. A second type of reaction leading to 17u-hydroxy-steroids is disclosed in copending application Serial No. 143,146, filed February 8, 1 950, which involves formation of the vici'nal bromohydrin from the 16,17-oxidopregnenes and -preg nanes and treatment of the bromohydrin with Raney nickel to replace the bromine with hydrogen. These methodsrepresent distinct advances in the art of preparing 17a-hydroxy compounds, and the vicinal bromohydrin procedure, at least, has been applied to the large scale manufacture of hydroxylated steroidal hormones of the adrenal cortex and intermediate products therefor. Notwithstanding the fact that the Raney nickel procedure obviated the use of dangerous and/ or relatively expensive materials, this procedure itself is subject to certain disadvantages, especially in view of later developments. For example, LiAll-h is generally used in conjunction with anhydrous ether, a relatively hazardous and expensive material when used in large scale operations. Further, to

a I I l A further object of the invention 18 to provide an improved process for the preparation of 17a-hydroxyice 2 pregnenes and allopregnanes directly from 'the corresponding bromo-17a=hydroxybromohydrin Another object is to provide a novel method for dehalogenating certain halogenated steroids.

An additional object is to provide a process for the preparation of Reichsteins Substance S in improved yield.

A still further object is to provide an improved process for the preparation'of allopregnanes possessing the ketol side-chain attached to ring D.

We have now found that the 16,17-bromohydrins of pregnenes which can be obtained from the corresponding epoxy derivatives, or the corresponding trans-dihaloallopregnanes, are readily dehalogenated 'by treatment with hydrogen in the presence of certain finely divided metallic catalysts. Thus, upon treatment of a 16-brom'o- 17a-hydroxy-pregnene in a suitable solvent, e. -,g., methanol, with hydrogen in the presence of palladium hydroxide supported on calcium carbonate or Raney nickel and at about 10 p. s. i. initial pressure, we have obtained practically the theoretical yield of the hydroxy-pregnene or allopregnane derivative.

We have found that depending upon the conditions employed, it is possible to stop the reaction atv the pregnene stage without substantial reduction of the double bond in'ring -B. Thus, by selecting a solvent for the reaction such that the bromohydrin is more soluble therein than the resulting debrominated A pregnen'e, the product obtained is substantially free of the allopregnan- 17a-ol derivative. Alternatively, we have made the surprising discovery that trans-5,'6-dih alo-16-bromo-17 hydroxypregnanes, upon treatment in accordance with bur invention, give rise to the corresponding 'A -pregnen- 17qol derivatives. Similarly, the trans-5,6-dihalo 16,17- epoxy-pregnane yield the corresponding 16,17-epox-y'5 pregnenes. We believe that the results we have obtained follow logically from the consideration thatin both instances the activity of the catalyst is affected, and, in a manner of speaking, poisoned. In the instance of a solvent in which the bromohydrin is more soluble than the debrominated product, the latter upon formation partially crystallizes out on the surface of the catalyst, thereby removing it from the reaction. In the alternative instance, wherein trans-5,6-dihalobromohydrins are treated, the dehalogenation occurs with the formation of three moles of hydrohalogen acid. As is well known, such acids are effective hydrolysis catalysts and may cause some hydrolysis of ester group's, giving rise to free hydroxy compounds, which in most cases are less soluble than the original esters. Accordingly, we believe that in either instance, the dehalogenation reaction being more "rapid than the reduction reaction is completed prior to the poisoning of the catalyst mass, and before substantial reduction occurs.

It is noted here that in all instances where the reaction has been permitted to proceed past the dehalogenati o'n stage, reduction of the double bond has resulted in complete conversion to the allopregnane derivative.

The process of our invention is carried out in the following general manner: The bromohydrin is dissolved, at least partially, in an amount of suitable solvent, with slight warming if desired, and to the solution about 2 to 5 parts of catalyst are added. The mixture is placed in the hydrogenation apparatus and maintained under a pressure of hydrogen between about 2 and about 10 p. s. i., preferably at about 25 C., room temperature, until the absorption of hydrogen has ceased. Thereafter, the reaction mixture is filtered from the spent catalyst, and the product is obtained from the clarified solution 0 in any suitable manner, e. g., by dilution with water,

evaporation to dryness, etc. The product so obtained is generally a usable intermediate in further synthetic opsure which varied from 10 to 2.5 p. s. i. 2% hours, the theoretical volume of hydrogen required erations. If desired, the product can be purified by recrystallization with a minimum of yield loss.

The following exampleswill illustrate the process of our invention. Example I.Preparatin of -pregnene-3BJ7oc-diol-20- v one 3-acetate 7 To a solution of 4 g. of l6-bromo 5-pregnene-3B,17a-

dibl-ZO-one 3-acetate in 200 cc. of absolute ethanol was added 12 g. of 2% palladium hydroxide on calcium carbonate, see Busch and Stove, Ber. 49, 1063 (1916). The mixture was reduced with hydrogen at a pressure which varied between and 2.5 p. s. i. After about two hours,

99.3% of the theoretical amount of hydrogen required to replace the 16-bromo group had been adsorbed and the reaction was stopped. The mass was-filtered and the filtrate was diluted with water. 1.0 g. of material, M. P. 210 to 215 C., was obtained. The filtered catalyst was extracted with methylene chloride and with methanol.

Upon evaporation of the solvents, 2.3 g. of material, melting at 225 to 230 C., was obtained. The mixture of this material with the watered out product melted at substantially the same temperaure. The total crude product, 100% yield, was recrystallized from a mixture of benzene and petroleum ether, B. R. 60 to 90 C. The purified material melted at 232 to 235 C. and wasrecovered in a 91% yield.

Removal of the bromine from this bromohydrin with Raney nickel alone, according .to the method described in I. A. C. S., 72, 5145 (1950), resulted in about an 80% yield of the identical product, 5-pregnene-3fi,l7a-diol-20- one 3-acetate.

Example 2 In a similar manner to that described in Example 1, when 2.5 g. of Raney nickel was used as a catalyst in place of the 2% palladium hydroxide, an 89% yield of the identical product was obtained.

Example 3.-Preparation 0f all0pregnan 3fi,17a,2I-tri0l- ZO-one 21 -acetate (a) By gentle warming, 3.7 g. of l6-bromo-5-pregnene- 3;3,l7a,2l-triol -one 2l-acetate was dissolved in 200 cc. of methanol. To this solution, 11.1 g. of 2% palladium hydroxide on calcium carbonate catalyst was added and the mixture reduced at 24.5 C. with hydrogen at a pres- After about to remove the l6-bromo group and saturate the double bond had been absorbed. The spent catalyst was filtered Example 4.Dehalogenation of 5a,6fi-dichl0ro-16abr0mo-all0pregnane-3;8,17a-di0l-20-one 3-acetate A mixture of 2 g. of.5a,6,8-dichloro-16a-bromo-allopregnane-Sfl,l7m-diol-20-one 3-acetate, which is prepared by HBr treatment of 5a,6fi-dichloro-l6,l7-epoxy-allopregnane-35-ol-20-one acetate, prepared as,disclosed in the application of Julian et al., Serial No. 430,442, filed May 17, 1954, 6.0 got 2% palladium hydroxide on calcium carbonate and 100 cc. of methanol was shaken with hydrogen at about 25 C. The pressure dropwithin the reaction vessel amounted to 6.75 p. s. i. The reaction mixture was heated to boiling and then filtered to remove spent catalyst. The filter cake was washed several times with hotmethanol and finally with methylene chloride. The combined filtrate and wash liquors were concentrated to turbidity and then set aside inan ice jbox'to crystallize. Upon filtration'ofthe' crystalline slurryand drying, 1.16

g. of shiny plates melting at 226 to 238 C., rotation (in chloroform, u =64.5, were obtained. This product gives a negative Beilstein test for halogen and a mixture with an authentic sample of 17a-hydroxy-pregnenolone acetate melted at 228 to 231 C.

The mother liquor upon concentration gave 0.14 g. of additional material, M. P. 265 to 270 C., which was identified as the free 17a-hydroxy-pregnenolone, since upon acetylation it was converted to a product identical with that first crop material obtainedabove. The combined yield of deh'alogenated product prepared in this manner is in excess of of the theoretical amount obtainable. Similar results were obtained whenthe 5,6- dibromo bromohydrin was used instead of the transdichloro bromohydrin.

Repetition of this experiment using cis-5,6-dichlorobromohydrin resulted in a pressure drop of only 3.3 p. s. i. The product was a mixture. The first crop, M. P. 232 to 235 0., contained 15.4% chlorine, theory for dichloro-17a-hydroxy-pregnenolone acetate=15.9%, and depressed the melting point of the starting material and of cis-5,6-dichloro-17u-hydroxy-pregnenolone acetate. When, instead of the trans-dichloro-bromohydrin, 2 g. of 5a,6p-dichloro-16,17 epoxyallopregnan 3,8-01-20-one acetate was used, 1.57 g. of 16,l7-epoxy-5-pregnen-3fl-ol- 20-one acetate, 93.5% of theory, was obtained.

An analogous experiment using 2 g. of 5a,6p-dichloro- 16,17-epoxy-allopregnane-3,20-dione gave 1.54 g., 90% of theory, of a product which gave no absorption in the ultraviolet. This product is 16,17-epoxy-allopregnane- 3,20-dione. I

In an analogous manner, 5a,6fi-dichloro-16-bromoallopregnane-3 3,17u,21-triol 20-one 21-acetate gives 5 pregnene-3 3,17u,21-triol-20-one 2l-acetate, M. P. 210 to 212, and 5oz,65-dichloro-lfi-bromo-allopregnane-17a,2l-

diol-3,20-dione 21-acetate gives 4-pregnene-17a,21-di0l- 3,20-dione 2l-acetate, Substance S-acetate.

It can readily be seen from the foregoing illustrative examples that an improved process has been provided for the preparation of l7a-hydroxy-steroids from the corresponding 16,17-epoxy steroids. Our invention, moreover, is not limited to the specific compounds treated inthe above examples, but is applicable to the preparation of 17a-hydroxy-20-oxosteroids from 16,17-epoxy-20-oxosteroids generally. Said steroids, as is well known in the art, can be converted to the corresponding 16-halogeno- 17a hydrdoxy-20-oxbsteroids, which then can be dehalogenated in excellent yield by the process of the present invention. The compounds which can be used may be substituted elsewhere in the steroid nucleus, e. g., at the 2-,-3-, 6-, 7-, ll-, 12- and/or 21-positions, which substituents may be halogen, oxo-hydroxyl and/or a substituent which is readily convertibleto hydroxyl as by hydrolysis. Halogen substituents, when present at other than the 5,6- and 16-positions, may be more or less completely removed during the reaction, and are, hence, preferably absent The starting'material can be saturated or unsaturated. Conjugated double bonds, because of their susceptibility to reductive influences, are preferably absent. V

Furthermore, as illustrated in the above examples, either the free hydroxy compounds or their esters can be used. In addition to the acetate esters, the propionates,

benzoates, naphthoates, nicotinates, hemisuccinates and will not poison the catalyst), for example, methylene chloride or mixtures of said suitable solvents, can be used.

7 The reaction is preferably effected at about 25". C., as a matter of convenience. Higher'temperatures, however, can be used to solubilize the bromohydrin if necessary. Further, the pressure of hydrogen under which the dehalogenation is carried out, can range from atmospheric to about 50 p. s. i. Preferably, a maximum of 10 p. s. i. should be used, at least at the commencement of the reaction.

We prefer to use a palladium hydroxide catalyst which is supported on calcium carbonate, although other alkaline earth carbonates, such as the strontium and barium carbonates, can be used. It is believed that the carbonate serves not only to support the palladium hydroxide (which during the hydrogenation is reduced to the active palladium moiety), but also to bind the hydrogen halide formed in the reaction. Other acid binding materials, e. g., barium oxide, can be used, but because of the wellknown sensitivity of halohydrins, and particularly 16- bromo-l7a-hydroxy-20-one steroids, to alkaline reagents, the catalyst supporting and acid binding material should preferably be a neutral reacting substance, e. g., an alkaline earth metal carbonate. Further, other noble metal catalysts, such as Raney nickel, can be used.

The 17a-l1YdIOXY-20-OXO products of the process of our invention are useful intermediates in the synthesis of valuable steroid hormones which are characterized by the ketol structure attached to ring D of the nucleus.

Our invention has been described and illustrated by recourse to certain specific examples. Further, for the purpose of clarification we have suggested certain theoretical explanations for the improvements obtained thereby. It should be distinctly understood, however, that our invention is not limited to any of said examples, or by the ultimate correctness of said explanations, except insofar as said limitations are contained in the claims appended hereto.

Having described the invention, what is claimed is:

1. The process which comprises treating a solution of a steroid selected from the class consisting of a,6;3-dichloro steroids of the allopregnane series, 5,6-dibromo steroids of the allopregnane series, 5,6-dibromo steroids of the pregnane series and 16-bromo-17a-hydroxy-A pregnenes with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal carbonate until the 5, 6 and 16 halogen substituents are removed.

2. The process of claim 1 in which the catalyst is palladium on an alkaline earth metal carbonate.

3. The process which comprises treating a solution of a l6-bromo-17m-hydroxy-A -pregnene with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal carbonate.

4. The process which comprises treating a solution of a 10,13-dimethyl-16-bromo-17a-hydroxy-20-keto-A -pregnene with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal carbonate.

5. The process of claim 4 in which the starting steroid is l6-bromo-5-pregnene-3fi,l7a,2l-triol-ZO-one 3-acetate.

6. The process which comprises treating a solution of a 5a,6fi-dichloro-ZO-keto-steroid of the allopregnane series with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal carbonate.

7. The process which comprises treating a solution of a 5a,6,B-dichloro-16-bromo-l7a-hydroxy-20-keto-steroid of the allopregnane series with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal carbonate.

8. The process of claim 7 in which the starting material is a 5u,6fi-dichloro-l6-bromo-17a-hydroxy-20-keto- 2l-acetoxy allopregnane.

9. The process of claim 8 in which the starting steroid is 5a,6B-dichloro-lfi-bromo-allopregnane-fifi,17a,21-triol- ZO-one Zl-acetate.

10. The process of claim 8 in which the starting material is 5a,6fl-dichloro-l6-bromo-allopregnane-1711,21-di0l- 3,2l-dione 21-acetate.

11. The process which comprises treating a solution of a 5a,6,6-dichloro-16,l7-epoxy-20-keto-steroid of the allopregnane series with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal carbonate.

12. The process which comprises treating a l6-bromo- 17a-hydroxy-20-keto-S- regnene in solution with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium and stopping the treatment when the removal or" the 16-bromo substituent is substantially complete.

13. The process which comprises treating a 5a,6fi-dichloro-allopregnane in solution with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal carbonate and stopping the treatment when the removal of the 5,6-halogen groups is substantially complete.

14. The process which comprises treating a 5a,6p-di chloro-16-bromo-17a-hydroxy-ZO-keto-allopregnane in solution with hydrogen in the presence of a catalyst selected from the class consisting of Raney nickel and palladium on an alkaline earth metal catalyst and stopping the treatment when the removal of 5, 6 and 16-halo groups is substantially complete.

OTHER REFERENCES Julian: JACS 72, pp. 5145-47, Nov. 1950. Julian: Recent Advances in Hormone Research (1951), pp. 204-05. 

1. THE PROCESS WHICH COMPRISES TREATING A SOLUTION OF A STEROID SELECTED FROM THE CLASS CONSISTING OF 5A,6B-DICHLORO STEROIDS OF THE ALLOPREGNANE SERIES, 5,6-DIBROMO STEROIDS OF THE ALLOPREGNANE SERIES, 5,6-DIBROMO STEROIDS OF THE PREGNANE SERIES AND 16-BROMO-17 A-HYDROXY-*5 PREGNENES WITH HYDROGEN IN THE PRESENCE OF A CATALYST SELECTED FORM THE CLAS CONSISTING OF RANEY NICKEL AND PALLADIUM ON AN ALKALINE EARTH METAL CARBONATE UNTIL AND 5,6 AND 16 HALOGEN SUBSTITUENTS ARE REMOVED. 